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Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes

Sjödahl, Gottfrid LU ; Abrahamsson, Johan LU ; Holmsten, Karin ; Bernardo, Carina LU orcid ; Chebil, Gunilla ; Eriksson, Pontus LU ; Johansson, Iva LU ; Kollberg, Petter LU ; Lindh, Claes and Lövgren, Kristina LU , et al. (2022) In European Urology 81(5). p.523-532
Abstract

BACKGROUND: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.

OBJECTIVE: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy.

DESIGN, SETTING, AND PARTICIPANTS: Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complete pathological response in the cystectomy specimen (ypT0N0) and survival were... (More)

BACKGROUND: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.

OBJECTIVE: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy.

DESIGN, SETTING, AND PARTICIPANTS: Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes.

RESULTS AND LIMITATIONS: Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11-0.79) and UroC tumors (HR 0.37, 95% CI: 0.14-0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response.

CONCLUSIONS: Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.

PATIENT SUMMARY: This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Basal/squamous, Bladder cancer, Chemotherapy, Cisplatin, Luminal, Molecular subtypes, Neoadjuvant, Osteopontin, Response, Signature, SPP1, Survival, Urothelial carcinoma
in
European Urology
volume
81
issue
5
pages
523 - 532
publisher
Elsevier
external identifiers
  • scopus:85119072622
  • pmid:34782206
ISSN
0302-2838
DOI
10.1016/j.eururo.2021.10.035
language
English
LU publication?
yes
id
aebdccb8-961a-473d-b2cc-8460073eff72
date added to LUP
2021-11-23 08:55:19
date last changed
2024-06-15 21:10:41
@article{aebdccb8-961a-473d-b2cc-8460073eff72,
  abstract     = {{<p>BACKGROUND: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.</p><p>OBJECTIVE: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy.</p><p>DESIGN, SETTING, AND PARTICIPANTS: Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation.</p><p>OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes.</p><p>RESULTS AND LIMITATIONS: Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11-0.79) and UroC tumors (HR 0.37, 95% CI: 0.14-0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response.</p><p>CONCLUSIONS: Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.</p><p>PATIENT SUMMARY: This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.</p>}},
  author       = {{Sjödahl, Gottfrid and Abrahamsson, Johan and Holmsten, Karin and Bernardo, Carina and Chebil, Gunilla and Eriksson, Pontus and Johansson, Iva and Kollberg, Petter and Lindh, Claes and Lövgren, Kristina and Marzouka, Nour al Dain and Olsson, Hans and Höglund, Mattias and Ullén, Anders and Liedberg, Fredrik}},
  issn         = {{0302-2838}},
  keywords     = {{Basal/squamous; Bladder cancer; Chemotherapy; Cisplatin; Luminal; Molecular subtypes; Neoadjuvant; Osteopontin; Response; Signature; SPP1; Survival; Urothelial carcinoma}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{523--532}},
  publisher    = {{Elsevier}},
  series       = {{European Urology}},
  title        = {{Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes}},
  url          = {{http://dx.doi.org/10.1016/j.eururo.2021.10.035}},
  doi          = {{10.1016/j.eururo.2021.10.035}},
  volume       = {{81}},
  year         = {{2022}},
}